The importance of splanchnic capacitance to blood pressure regulation has long been recognized, but clinical research has lagged behind because of limitations in experimental methodology. We have put together a research team (of physiologists, clinical pharmacologists, cardiologists, biomedical engineers and statisticians) with access to unique resources (ganglionic blockade with trimethaphan, determination of segmental volume changes with nuclear medicine and impedance, patients with autonomic failure) to make progress in this field. Substantial evidence from animal studies indicates that the splanchnic circulation contributes to hypertension. Our preliminary studies in hypertensive subjects indicate that sympathetic withdrawal with trimethaphan lowers blood pressure by reducing stroke volume. This suggests that sympathetically mediated contraction of splanchnic capacitance contributes to hypertension in humans, a hypothesis that we will test in Specific Aim 1. On the other hand, reflex contraction of splanchnic capacitance is an important compensatory mechanism to maintain adequate blood pressure during stimuli such as upright posture or heat stress. Patients with autonomic failure lack these compensatory reflexes and provide a unique resource to study these phenomena. E.g., autonomic failure patients are sensitive to heat stress because they are unable to dissipate heat or to compensate with reflex sympathetic activation. In Specific Aim 2 we will take advantage of these abnormalities to determine if controlled heat application can be used to treat the supine hypertension of autonomic failure. Finally, the clinical picture of autonomic failure is dominated by orthostatic hypotension due primarily to splanchnic venous pooling. We have developed a device that detects upright posture and automatically inflates an abdominal binder with a servo controller that maintains inflation pressure to 40 mm Hg. Our preliminary results suggest that this automated abdominal binder is as effective as midodrine, the current standard of care in improving orthostatic tolerance. We will test the efficacy of this device in Specific Aim 3.